Process for preparation of 6-aminopenicillanic acid

ABSTRACT

A process for the preparation of 6-aminopenicillanic acid is described which comprises reacting a natural penicillin with a phosphorus halide to protect the carboxyl group of the natural penicillin and thereafter reacting the protected penicillin with an acid halide to form the corresponding penicillin imino halide, reacting the imino halide with an alcohol to form an imino ether and subsequent hydrolysis or alcoholysis to 6-aminopenicillanic acid.

United States Patent Sellstedt 1 July 22, 1975 PROCESS FOR PREPARATIONOF 6-AMINOPENICILLANIC ACID Inventor: John H. Sellstedt, King ofPrussia,

Assignee: American Home Products Corporation, New York, NY.

Filed: Oct. 4, 1971 Appl. No.: 186,397

U.S. Cl 260/239.1; 260/306.7 E; 424/271 Int. Cl C07d 99/16 Field ofSearch 260/239.1, 935, 306.7 E

References Cited UNITED STATES PATENTS 11/1952 Young 260/112 11/1953Young 260/935 12/1969 Dever et a1. 260/935 3/1970 Weissenburger et a1.260/306.7

5/1974 lshimaru 260/239.1

OTHER PUBLICATIONS The Merck Index, 7th Ed., p. 140 Modern DrugEncyclopedia, pp. 541-542.

Primary ExaminerDonald G. Daus Assistant Examiner-Jose Tovar [57]ABSTRACT 8 Claims, No Drawings PROCESSFOR PREPARATION OF6-AMINOPENICILLANIC ACID The novel process of the present invention forthe preparation of 6-aminopenicillanic acid (hereinafter 6-APA)comprises forming a carboxylic acid protecting derivative of a natural6-acylaminopenicillanic acid by reacting a trivalent or pentavalentphosphorus halide, with a 6-acylaminopenicillanic acid, reacting theformed anhydride compound with an acid halide to form an imino halidecompound and reacting this compound with an alcohol to introduce anether group on the imino carbon and reforming the free carboxylic acidgroup and splitting the imino bond to form 6-APA.

The process of this invention may be represented by sisting of a(lower)alkoxy radical, aryloxy radical, aryl(lower)alkyloxy radical andhalogen; and R1 and R may be joined together to form the ring R isoxygen n is a number which is either 0 or 1; m is a number from 0 to 6;X is a halogen atom.

The term halogen as used herein means chlorine, bromine, iodine andfluorine. The term (lower)alkoxy means a straight chain or branch chainhydrocarbon radical having C to C carbons as illustrated by thefollowing scheme: l5 methoxy, ethoxy, propoxy, pentoxy, isobutoxy, etc.

o R1 H s cu, RC-NH +x P-R Solvent cu O=-NCO2M (R l ll 0 ll s cu, RCNH RIll The protected penicillin of formula III may be converted to 6-APA inaccordance with the procedure described in South African Pat. No.672,927, the disclosure of which is incorporated herein by reference.

For the compound of formula I any pencillin can be,

used. As a practical matter, pencillins are used which can be obtainedby microbiological processes such as those penicillins wherein R isselected from the class consisting of a lower aliphatic radical havingup to and including 7 carbon atoms, aryl(lower)alkyl, aryloxy(-lower)alkyl, substituted aryl(lower)alkyl and substitutedaryloxy(lower)alkyl. Specific illustrations of R as an aliphatic radicalinclude methyl, propyl, Z-pentenyl (penicillin F), n-heptyl (penicillinK), and namyl(dihydro'penicillin F). The terms aryl(lower)alkyl areillustrated by benzyl (penicillin G), p-

hydroxybenzyl (penicillin 'X), p-aminobenzyl (penicil- III The term anaryloxy radical" is illustrated by phenoxy, naphthoxy and substitutedderivatives thereof. The term aryl(lower)alkyloxy" is illustrated bybenzyloxy, phenethyloxy, etc.

Illustrative of specific compounds falling within the scope of formulaII are phosphorus oxychloride, phosphorus trichloride, diphenylchlorophosphate, diethyl chlorophosphate, phenyl dichlorophosphate,ethyl dichlorophosphate, ethylene chlorophosphate, diethylchlorophosphite, ethyl dichlorophosphite, ehtylene chlorophosphite.

The reaction of a compound of formula I with a compound of formula II ispreferably carried out in an anhydrous inert, aprotic solvent.Illustrative of suitable solvents are chloroform, methylene chloride,dichloroethane, tetrahydrofuran, etc. The process of protecting thecarboxyl group is carried out at a temperature in the range of about toabout +l0C., preferably -l0 to +lOC. and the molar ratio of a compoundof formula I to a compound of formula II is about 0.5:1 to 3:1,preferably about 1:1.

The compounds of formula H] are converted to 6-APA in accordance withthe following reaction scheme:

(Rah

acid halide base Examples of suitable acid halides are phosphoruspentachloride, phosgene, phosphorus oxychloride, oxalyl chloride,p-toluene sulfonic acid chloride, etc. The preferred acid halides arephosphorus pentachloride and phosphorus oxychloride. The reaction of acompound of formula lll with an acid halide is carried out in thepresence of acid binding agents such as a tertiary amine base asexemplified by N,N-dimethylaniline, quinoline, pyridine, triethylamine,N-ethylmorpholine, etc.

The reaction of the acid halide with a compound of formula III iscarried out at a temperature in the range of 40 to +30C, depending onthe reactivity of the particular acid halide used. A slight excess ofacid halide, not more than about l%, is used in the formation of acompound of formula IV.

The alcohol represented by R OH is preferably selected from the groupconsisting of alkanols having C to C carbons (e.g. methanol, ethanol,butanol, isobutanol, etc.) and aryl (lower)alkyl alcohols such as benzylalcohol, 2-phenyl-ethanol, etc. The introduction of the OR, group on theimino carbon atom is preferably carried out at a temperature of between40 and 10C. Once the imino ether of formula V is formed, the imino bondand the protective group on the carboxyl group is split off byhydrolysis or alcoholysis.

The following examples are illustrative of the process of the presentinvention:

EXAMPLE I Potassium Penicillin G (60.0 g., 0.161 mole) is stirred inanhydrous methylene chloride (250 ml.), and the mixture is cooled downto 30C. Dimethylaniline (44 ml., 0.348 mole) is added followed by adropwise addition of phosphorous oxychloride (l6.3 ml., 0.178 mole) over20 minutes at 30C. The solution is stirred an additional hour at 30C,and then phosphorus pentachloride (26.2 g., 0.174 mole) is added over 2to 3 minutes at 39 to 35C. The solution is stirred for 2 hours at 35C,and butanol (250 ml.) is added as rapidly as possible while keeping thetemperature at 30 to 35C, with acetone-dry ice cooling. The solution isstirred for 3 hours at 35C and water (225 ml.) is added. The pH isadjusted to 4 at 5C., by addition of sodium carbonate, and the resultingmixture is seeded with 6-APA and stirred at 05C., overnight. The pH isreadjusted to 4 with 35% sodium hydroxide and the mixture is filtered.The cake is washed with 1:1 acetone-water (10 ml.) and acetone (2 X 10ml.), giving white crystals (3.2 g.). The infrared spectrum is identicalwith an authentic sample of 6-APA.

EXAMPLE 2 6-APA may be obtained following the procedure of Example 1using penicillin V in place of penicillin G and using ethyldichlorophosphite in place of phosphorous oxychloride.

As previously indicated, an excess of a penicillin of formula I may bereacted with a phosphorus halide of formula ll to form a polypenicillin-phosphorus anhydride compound. Such compounds would berepresented by the formula These poly penicillin-phosphorus anhydridesare converted to 6-APA following the same reaction scheme illustrated bygoing from formula III to 6-APA as previously described.

What is claimed is:

l. A compound of the formula 5 ca R-C-NH fCH R,

O= N co.-i -R R is =0 (oxygen); n is a number which is 0 or l; and

m is a number from 0 to 6. 2. A compound according to claim 1 wherein Ris benzyl.

3. A compound according to claim 1 wherein R is phenoxymethyl.

4. A compound according to claim 2 which is:

S CH

5. A compound having a formula selected from the group consisting of:

5 CH K TC; R N CO2PR2 wherein:

R is selected from the class consisting of n-heptyl, namyl, Z-pentenyl,benzyl, phenoxymethyl, p-

R is (oxygen); R is selected from the class consisting ofphenyl(lower)alkyl, and lower( alkyl); n is a number which is 0 or 1; mis a number which is 0 through 6. 6. A compound according to claimwherein R and R are each halogen.

7. A compound according to claim 5 which is:

8. A compound according to claim 5 which is the hydrochloride salt ofPage 2 Of 2 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OFCORRECTION PATENT NO. 6,1 0

DATED July 22, 1975 |N\/ ENTOR( I John H. Sellstedt It is certifiedthaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 4 (claim 1) change the first structural formula in claim toSigned and Sealed this [SEAL] foam f y 1976 A nest:

RUTH C. MASON Arresting RSHALL DANN mnmrssmner nflalrinrx and Trademarks

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 whereinR is benzyl.
 3. A compound according to claim 1 wherein R isphenoxymethyl.
 4. A compound according to claim 2 which is:
 5. Acompound having a formula selected from the group consisting of:
 6. Acompound according to claim 5 wherein R1 and R2 are each halogen.
 7. Acompound according to claim 5 which is:
 8. A compound according to claim5 which is the hydrochloride salt of